Thrombocythemia 1

Summary

Thrombocythemia 1 (MONDO:0008554) is a disease caused by THPO (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: THPO (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 54

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	thrombocythemia 1
Mondo ID	MONDO:0008554
OMIM	187950
UMLS	C3277671
MedGen	479301
GARD	0024630
Is cancer (heuristic)	no

Also known as: THCYT1 · thrombocythemia 1 · thrombocythemia type 1 · thrombocythemia, somatic

Data availability: 54 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › blood platelet disease › thrombocytosis disease › familial thrombocytosis › thrombocythemia 1

Related subtypes (2): thrombocythemia 2, thrombocythemia 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

54 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 12 conflicting classifications of pathogenicity, 5 benign, 3 likely pathogenic, 3 benign/likely benign, 2 pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1028735	NM_004343.4(CALR):c.1154_1155insTTGTC (p.Lys385fs)	CALR	Pathogenic	criteria provided, multiple submitters, no conflicts
97006	NM_004343.3(CALR):c.1092_1143del52 (p.Leu367Thrfs)	CALR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872935	NM_000460.4(THPO):c.-47del	THPO	Pathogenic	criteria provided, single submitter
9508	NM_000460.4(THPO):c.13+1G>C	THPO	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208237	NC_000014.9:g.95696766_96390792dup	LOC130056392	Likely pathogenic	criteria provided, single submitter
9510	NM_000460.4(THPO):c.-31G>T	THPO	Likely pathogenic	criteria provided, single submitter
975832	NM_000460.4(THPO):c.13+2T>C	THPO	Likely pathogenic	no assertion criteria provided
1336169	NM_005475.3(SH2B3):c.464C>T (p.Pro155Leu)	SH2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
30445	NM_005475.3(SH2B3):c.622G>C (p.Glu208Gln)	SH2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
619973	NM_005475.3(SH2B3):c.1183G>A (p.Glu395Lys)	SH2B3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
197671	NM_000460.4(THPO):c.356G>A (p.Arg119His)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
286872	NM_000460.4(THPO):c.*18G>A	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
344370	NM_000460.4(THPO):c.889A>G (p.Thr297Ala)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
344374	NM_000460.4(THPO):c.-56G>A	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3456248	NM_000460.4(THPO):c.531A>C (p.Pro177=)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
497712	NM_000460.4(THPO):c.183G>T (p.Leu61=)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
764293	NM_000460.4(THPO):c.579C>T (p.Asn193=)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
902535	NM_000460.4(THPO):c.963C>T (p.His321=)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
903386	NM_000460.4(THPO):c.310C>A (p.Pro104Thr)	THPO	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240158	NM_005373.3(MPL):c.92T>C (p.Leu31Pro)	MPL	Uncertain significance	criteria provided, single submitter
3574256	NM_005475.3(SH2B3):c.1696C>T (p.Arg566Trp)	SH2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
501686	NM_005475.3(SH2B3):c.1198G>A (p.Glu400Lys)	SH2B3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1185024	NM_000460.4(THPO):c.233A>G (p.Glu78Gly)	THPO	Uncertain significance	criteria provided, single submitter
2442041	NM_000460.4(THPO):c.482G>A (p.Arg161His)	THPO	Uncertain significance	criteria provided, multiple submitters, no conflicts
281426	NM_000460.4(THPO):c.518T>C (p.Val173Ala)	THPO	Uncertain significance	criteria provided, multiple submitters, no conflicts
344365	NM_000460.4(THPO):c.*500A>G	THPO	Uncertain significance	criteria provided, single submitter
344367	NM_000460.4(THPO):c.*404G>A	THPO	Uncertain significance	criteria provided, single submitter
344371	NM_000460.4(THPO):c.671G>A (p.Gly224Glu)	THPO	Uncertain significance	criteria provided, single submitter
344372	NM_000460.4(THPO):c.517G>A (p.Val173Ile)	THPO	Uncertain significance	criteria provided, multiple submitters, no conflicts
344373	NM_000460.4(THPO):c.303A>G (p.Gln101=)	THPO	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
THPO	Strong	Autosomal dominant	thrombocythemia 1	9
SH2B3	No Known Disease Relationship	Unknown	thrombocythemia 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
THPO	Orphanet:329319	Thrombocythemia with distal limb defects
THPO	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
THPO	Orphanet:397692	Hereditary isolated aplastic anemia
THPO	Orphanet:71493	Familial thrombocytosis
SH2B3	Orphanet:3318	Essential thrombocythemia
SH2B3	Orphanet:391366	Growth retardation-mild developmental delay-chronic hepatitis syndrome
CALR	Orphanet:131	Budd-Chiari syndrome
CALR	Orphanet:3318	Essential thrombocythemia
CALR	Orphanet:824	Primary myelofibrosis
MPL	Orphanet:3318	Essential thrombocythemia
MPL	Orphanet:3319	Congenital amegakaryocytic thrombocytopenia
MPL	Orphanet:397692	Hereditary isolated aplastic anemia
MPL	Orphanet:71493	Familial thrombocytosis
MPL	Orphanet:824	Primary myelofibrosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
THPO	HGNC:11795	ENSG00000090534	P40225	Thrombopoietin	gencc,clinvar
SH2B3	HGNC:29605	ENSG00000111252	Q9UQQ2	SH2B adapter protein 3	gencc,clinvar
CALR	HGNC:1455	ENSG00000179218	P27797	Calreticulin	clinvar
MPL	HGNC:7217	ENSG00000117400	P40238	Thrombopoietin receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
THPO	Thrombopoietin	Lineage-specific cytokine affecting the proliferation and maturation of megakaryocytes from their committed progenitor cells.
SH2B3	SH2B adapter protein 3	Links T-cell receptor activation signal to phospholipase C-gamma-1, GRB2 and phosphatidylinositol 3-kinase.
CALR	Calreticulin	Calcium-binding chaperone that promotes folding, oligomeric assembly and quality control in the endoplasmic reticulum (ER) via the calreticulin/calnexin cycle.
MPL	Thrombopoietin receptor	Receptor for thrombopoietin that regulates hematopoietic stem cell renewal, megakaryocyte differentiation, and platelet formation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	7.3×	0.318
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
THPO	Other/Unknown	no		EPO_TPO, Thrombopoietin, 4_helix_cytokine-like_core
SH2B3	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
CALR	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, Calreticulin
MPL	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Ig-like_fold

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	2
mononuclear cell	2
liver	1
right hemisphere of cerebellum	1
right lobe of liver	1
leukocyte	1
left lobe of thyroid gland	1
right lobe of thyroid gland	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
THPO	157	tissue_specific	yes	right lobe of liver, liver, right hemisphere of cerebellum
SH2B3	260	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
CALR	289	ubiquitous	marker	stromal cell of endometrium, left lobe of thyroid gland, right lobe of thyroid gland
MPL	166	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, mononuclear cell, monocyte

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CALR	6,185
SH2B3	1,617
THPO	1,375
MPL	1,039

Intra-cohort edges

A	B	Sources
CALR	MPL	string_interaction
MPL	SH2B3	string_interaction
MPL	THPO	intact, string_interaction
SH2B3	THPO	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CALR	P27797	10
THPO	P40225	3
MPL	P40238	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH2B3	Q9UQQ2	63.45

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 37. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Platelet Aggregation (Plug Formation)	2	219.6×	0.001	THPO, MPL
Virus Assembly and Release	1	1427.5×	0.009	CALR
Assembly of Viral Components at the Budding Site	1	1427.5×	0.009	CALR
Scavenging by Class F Receptors	1	475.8×	0.016	CALR
ATF6 (ATF6-alpha) activates chaperones	1	475.8×	0.016	CALR
ATF6 (ATF6-alpha) activates chaperone genes	1	285.5×	0.022	CALR
Calnexin/calreticulin cycle	1	178.4×	0.025	CALR
Negative regulation of FLT3	1	178.4×	0.025	SH2B3
Regulation of KIT signaling	1	150.3×	0.025	SH2B3
Scavenging by Class A Receptors	1	150.3×	0.025	CALR
Binding and Uptake of Ligands by Scavenger Receptors	1	135.9×	0.025	CALR
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	1	105.7×	0.028	CALR
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	1	98.5×	0.028	CALR
Unfolded Protein Response (UPR)	1	89.2×	0.028	CALR
FLT3 Signaling	1	86.5×	0.028	SH2B3
Antigen processing-Cross presentation	1	79.3×	0.029	CALR
Signaling by SCF-KIT	1	62.1×	0.035	SH2B3
Maturation of DENV proteins	1	52.9×	0.039	CALR
Influenza Infection	1	43.9×	0.044	CALR
ER-Phagosome pathway	1	32.4×	0.056	CALR
Immune System	2	6.5×	0.057	SH2B3, CALR
Class I MHC mediated antigen processing & presentation	1	17.5×	0.094	CALR
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.095	SH2B3
Asparagine N-linked glycosylation	1	15.0×	0.100	CALR
Signaling by Receptor Tyrosine Kinases	1	12.9×	0.111	SH2B3
Cytokine Signaling in Immune system	1	10.2×	0.135	SH2B3
Cellular responses to stress	1	9.2×	0.140	CALR
Hemostasis	1	9.0×	0.140	SH2B3
Vesicle-mediated transport	1	8.7×	0.140	CALR
Cellular responses to stimuli	1	7.9×	0.147	CALR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
thrombopoietin-mediated signaling pathway	3	1579.9×	2e-08	THPO, SH2B3, MPL
monocyte homeostasis	2	2808.7×	5e-06	SH2B3, MPL
neutrophil homeostasis	2	766.0×	6e-05	SH2B3, MPL
megakaryocyte development	2	351.1×	2e-04	THPO, SH2B3
basophil homeostasis	1	4213.0×	0.004	MPL
negative regulation of Kit signaling pathway	1	2106.5×	0.005	SH2B3
positive regulation of platelet formation	1	2106.5×	0.005	MPL
response to biphenyl	1	1404.3×	0.006	CALR
eosinophil homeostasis	1	1404.3×	0.006	MPL
negative regulation of intracellular steroid hormone receptor signaling pathway	1	1053.2×	0.006	CALR
nuclear receptor-mediated glucocorticoid signaling pathway	1	1053.2×	0.006	CALR
obsolete sequestering of calcium ion	1	842.6×	0.006	CALR
negative regulation of receptor signaling pathway via STAT	1	842.6×	0.006	SH2B3
peptide antigen assembly with MHC class I protein complex	1	702.2×	0.006	CALR
cellular response to interleukin-3	1	702.2×	0.006	SH2B3
negative regulation of response to cytokine stimulus	1	702.2×	0.006	SH2B3
regulation of meiotic nuclear division	1	601.9×	0.006	CALR
negative regulation of chemokine-mediated signaling pathway	1	601.9×	0.006	SH2B3
negative regulation of trophoblast cell migration	1	601.9×	0.006	CALR
response to glycoside	1	601.9×	0.006	CALR
positive regulation of dendritic cell chemotaxis	1	526.6×	0.007	CALR
positive regulation of lymphocyte proliferation	1	468.1×	0.007	MPL
positive regulation of hematopoietic stem cell proliferation	1	468.1×	0.007	THPO
negative regulation of retinoic acid receptor signaling pathway	1	383.0×	0.008	CALR
protein folding in endoplasmic reticulum	1	351.1×	0.008	CALR
positive regulation of megakaryocyte differentiation	1	351.1×	0.008	THPO
negative regulation of platelet aggregation	1	351.1×	0.008	SH2B3
cellular response to electrical stimulus	1	324.1×	0.008	CALR
megakaryocyte differentiation	1	300.9×	0.009	THPO
cellular response to lithium ion	1	280.9×	0.009	CALR

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
THPO	PROGESTERONE
MPL	LUSUTROMBOPAG

Top cohort targets by molecule count

Symbol	Molecules	Max phase
THPO	103	4
MPL	2	4
SH2B3	0	0
CALR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	THPO
CLOTRIMAZOLE	4	THPO
COLCHICINE	4	THPO
SALMETEROL XINAFOATE	4	THPO
BRETYLIUM TOSYLATE	4	THPO
SULFAPHENAZOLE	4	THPO
AMOXAPINE	4	THPO
DICYCLOMINE	4	THPO
NICARDIPINE HYDROCHLORIDE	4	THPO
CARBIDOPA ANHYDROUS	4	THPO
EPINEPHRINE BITARTRATE	4	THPO
BUDESONIDE	4	THPO
CHLORZOXAZONE	4	THPO
PIMOZIDE	4	THPO
NICLOSAMIDE	4	THPO
AZACITIDINE	4	THPO
TRIFLUPERIDOL	4	THPO
CAPTOPRIL	4	THPO
KETOCONAZOLE	4	THPO
PSEUDOEPHEDRINE	4	THPO
CLEMASTINE	4	THPO
RIBAVIRIN	4	THPO
SERTRALINE HYDROCHLORIDE	4	THPO
TERFENADINE	4	THPO
FLUOROURACIL	4	THPO
NIFEDIPINE	4	THPO
PRAZOSIN	4	THPO
MAPROTILINE	4	THPO
MECAMYLAMINE	4	THPO
HYDRALAZINE	4	THPO

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MPL	23	Functional:15, Binding:7, ADMET:1
THPO	2	Functional:2
CALR	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PROGESTERONE	4	THPO
CLOTRIMAZOLE	4	THPO
COLCHICINE	4	THPO
SALMETEROL XINAFOATE	4	THPO
BRETYLIUM TOSYLATE	4	THPO
SULFAPHENAZOLE	4	THPO
AMOXAPINE	4	THPO
DICYCLOMINE	4	THPO
NICARDIPINE HYDROCHLORIDE	4	THPO
CARBIDOPA ANHYDROUS	4	THPO
EPINEPHRINE BITARTRATE	4	THPO
BUDESONIDE	4	THPO
CHLORZOXAZONE	4	THPO
PIMOZIDE	4	THPO
NICLOSAMIDE	4	THPO
AZACITIDINE	4	THPO
TRIFLUPERIDOL	4	THPO
CAPTOPRIL	4	THPO
KETOCONAZOLE	4	THPO
PSEUDOEPHEDRINE	4	THPO
CLEMASTINE	4	THPO
RIBAVIRIN	4	THPO
SERTRALINE HYDROCHLORIDE	4	THPO
TERFENADINE	4	THPO
FLUOROURACIL	4	THPO
NIFEDIPINE	4	THPO
PRAZOSIN	4	THPO
MAPROTILINE	4	THPO
MECAMYLAMINE	4	THPO
HYDRALAZINE	4	THPO

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	THPO, MPL
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	SH2B3, CALR

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SH2B3	0	THPO
CALR	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.